This invention relates to piperidone derivatives which are neurokinin receptor antagonists of utility in the treatment of a variety of medical conditions including, for example, urinary incontinence, asthma and related conditions. More particularly this invention relates to certain 5-aryl-5-(azabicyclo[3.1.0]hexane alkyl)-N-substituted-piperidone derivatives, to processes for their preparation, compositions thereof and their use in medicine.
According to the specification of our co-pending International patent application WO 96/05193 we describe and claim a series of 5-aryl-5-azetidinylalkyl-piperidone derivatives. The compounds are antagonists of tachykinins, including neurokinin A, neurokinin B and Substance P, acting at the human neurokinin-1 (NK.sub.1), neurokinin-2 (NK.sub.2) or neurokinin-3 (NK.sub.3) receptor, and are therefore potentially useful for preventing or treating a variety of medical conditions in which these receptors have been implicated, including inflammatory diseases such as arthritis, psoriasis, asthma or inflammatory bowel disease; central nervous system disorders such as anxiety, depression, dementia or psychosis; gastro-intestinal disorders such as functional bowel disease, irritable bowel syndrome, gastro-oesophageal reflux, faceal incontinence, colitis, Crohn's disease or diseases caused by Helicobacter pylori or other bacteria; urogenital tract disorders such as incontinence, hyperreflexia, impotence or cystitis; pulmonary disorders such as chronic obstructive airways disease; allergies such as eczma, contact dermatitis, atopic dermatitis, urticaria, rhinitis or hypersensitivity disorders such as to poison ivy; vasospastic diseases such as angina or Reynaud's disease; proliferative disorders such as cancer or a disorder involving fibroblast proliferation; fibrosing or coliagen diseases such as scleroderma or eosinophillic fascioliasis; reflux sympathetic dystrophy such as shoulder/hand syndrome; addiction disorders such as alcoholism; stress-related somatic disorders; peripheral neuropathies such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burns, herpetic neuralgia or post herpetic neuralgia; neuropathological disorders such as Alzheimer's disease or multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus erythematosis; rheumatic diseases such as fibrositis or emesis; opthalmic diseases such as retinopathy; viral diseases such as colds and influenza; cough; acute or chronic pain or migraine.
The present invention provides a further series of related compounds wherein the piperidone-5-substituent is an azabicyclo[3.1.0]hexanealkyl-group. Also claimed are the corresponding di-one (glutarimide) derivatives. The compounds are potent and selective antagonists of tachykinins including neurokinin A, neurokinin B and substance P, active at the human NK.sub.1, NK.sub.2 and NK.sub.3 receptors and they thus have potential utility in any of the disease states indicated above including, in particular treating or preventing inflammatory diseases such as arthritis, psoriasis, asthma or inflammatory bowel disease; central nervous system disorders such as anxiety, depression, dementia or psychosis; gastrointestinal disorders such as functional bowel disease, irritable bowel syndrome, gastro-oesophageal reflux, faecal incontinence, colitis or Crohn's disease; urogenital tract disorders such as incontinence or cystisis; pulmonary disorders such as chronic obstructive airways disease; allergies such as eczema, contact dermatitis or rhinitis; hypersensitivity disorders such as to poison ivy; peripheral neuropathies such as diabetic neuropathy, neuralgia, causalgia, painful neuropathy, burns, herpetic neuralgia or post-herpetic neuralgia; cough or acute or chronic pain.